1. Field of the Invention
The present invention relates to novel salt forms of zolpidem and to pharmaceutical compositions and methods of treatment containing the same.
2. Description of the Related Arts
Zolpidem is a known hypnotic agent having the following formula. ##STR1##
It has been marketed in solid dosage forms for peroral application (tablets) under the trade marks AMBIEN.RTM. and STILNOX.RTM.. As the active substance in these pharmaceutical dosage forms, zolpidem is present in the form of a salt with natural L(+)tartaric acid ((2R,3R)-2,3-dihydroxybutanedicarboxylic acid) wherein the molar ratio of zolpidem and tartaric acid in the salt is 2:1. This salt is conventionally called zolpidem hemitartrate but more a correct denomination thereof, which will be used hereinafter, is zolpidem tartrate.
The zolpidem free base was disclosed generically in EP 50563 of Synthelabo. The zolpidem tartrate used in the commercial products, along with an improved synthesis scheme, was subsequently disclosed in EP 251859 (U.S. Pat. No. 4,794,185). It is believed that the process set forth in this patent corresponds to the commercial process presently used for the production of zolpidem. An example therein shows the production of zolpidem and the formation of the tartrate salt. Specifically, 25 g of zolpidem free base is dissolved in 180 ml of methanol and combined with 60 ml of a methanol solution containing 6.1 g of tartaric acid (a 1:2 molar ratio) and then allowing the mixed solution to crystallize. The crystalline product is reported to have a melting point of 197.degree. C. The specific details of how the crystallization is performed are not disclosed.
The European Pharmacopoeia, Monograph No. 1999:1280, states that zolpidem tartrate is characterized as a white or almost white crystalline powder, hygroscopic, slightly soluble in water, sparingly soluble in methanol, and practically insoluble in methylene chloride. For identification purposes, a Pharmacopoeial reference standard, namely zolpidem tartrate CRS, is a commercially available substance that serves as the reference for any analysis or comparison.
The crystal structure of the zolpidem tartrate has also been published in an article of P. George et al. (Zolpidem and related compounds, in: Imidazopyridines in Sleep Disorders, edited by J. P. Sauvanet et al., Raven Press New York 1988, p. 11 ff.), the entire contents of which is incorporated herein by reference. When interpreting the results of single crystal X-ray structure analysis, it was concluded by the above authors that the crystal lattice repeating unit contained two layers of zolpidem, one protonated (and thus ionically bound to the tartaric acid moiety) and one unprotonated (and thus bound by other than ionic bonding).
However, studies conducted by the present inventors have revealed that forming the zolpidem tartrate salt is difficult. The method of manufacturing zolpidem tartrate described in the documents discussed above comprises crystallization of a mixed solution of zolpidem free base and tartaric acid (in 2:1 molar ratio) in methanol. The present inventors repeated this method with the aim to test the ruggedness of the production method in modeling situations encountered on an industrial scale (changes in temperature regimen, concentration of components, quality of solvent used, etc.) and found out that the crystallization process is highly irreproducible. Proper formation of crystalline zolpidem tartrate in desired yield and quality is highly dependent on strict control and maintaining the optimum crystallization conditions, quality of starting materials (namely content of water in methanol) and molar ratio of zolpidem and tartaric acid. It often happened that, from batch to batch and under otherwise the same conditions, crystals were not formed at the preselected temperature in a reasonable time and it was necessary to continue with cooling the mixture to lower temperatures to obtain a solid product. At temperatures lower than ambient, impurities present in the starting materials can also coprecipitate and thus decrease the quality of the obtained product. Also, and sometimes unpredictably, another salt is obtained instead of the desired tartrate. Thus, it is highly unpredictable to estimate whether and when the desired product will be obtained from the solution and what the yield and quality of the product from a production batch will be.
Moreover, the present inventors have found that the known zolpidem tartrate has low physical stability. That is, the application of energy such as mechanical grinding, heat, etc., to the known zolpidem tartrate can readily cause the crystal structure to change forms and in particular can cause the release of zolpidem free base. In retrospect, the instability of the zolpidem tartrate makes sense in view of the unprotonated zolpidem layer within the crystal lattice and the fact that zolpidem is a very weak base. This physical instability can lead to unintended changes in the zolpidem salt form during manufacture or storage. For example, during storage the zolpidem tartrate could begin to decompose into a mixture of zolpidem hydrogen tartrate (1:1 ratio of zolpidem to tartaric acid) and zolpidem free base. The zolpidem free base is not as water soluble as the zolpidem tartrate or zolpidem hydrogen tartrate and thus may not be taken up by the body in vivo thereby reducing the bioavailability.
Accordingly, it would be desirable to have a zolpidem salt form that exhibits greater physical stability than the known zolpidem tartrate. It would also be desirable to have a zolpidem salt form that is readily reproducible, especially on an industrial scale.